Search

Obesity is a highly prevalent disease and providers are expected to offer or refer patients for weight management yet increasingly fewer clinical visits address obesity. Challenges to offering care are known but less is known about referrals and how specialists who treat obesity-related comorbidities address care and referrals. This study explored perceptions of primary care providers (PCPs) and specialty providers regarding care and referrals for weight management, specifically referrals to programs in the community setting. A qualitative design was used to interview 33 PCPs (mean age 54 years) and 31 specialists (cardiology, gynecology, endocrinology, and orthopedics [mean age 62 years]) in the USA during 2019. Each interview was conducted by telephone, audio-recorded, and transcribed verbatim. Inductive analysis was used and followed the constant comparative method. Four themes emerged from the data including (a) Clinical guidelines and provider discretion influence obesity care; (b) Facilitators and barriers to discussing weight and small step strategies; (c) Informal referrals are made for weight management in community settings; and (d) Opportunities and challenges for integrating clinical and community services for weight management. Facilitating referrals to effective programs, ideally with a feedback loop could coordinate care and enhance accountability, but education, compliance, and cost issues need addressed. Care may be offered but not be well-aligned with clinical guidelines. Knowledge gaps regarding community programs’ offerings and efficacy were evident. Referrals could be systematically promoted, facilitated, and tracked to advance weight management objectives.

This study examined the associations between overall diet quality and the risk of dementia in a rural cohort among the oldest old. Included in this prospective cohort study were 2232 participants aged ≥ 80 years and dementia-free at the baseline according to the Geisinger Rural Aging Study (GRAS), a longitudinal cohort in rural Pennsylvania. In 2009, diet quality was assessed by a validated dietary screening tool (DST). Incident cases of dementia during 2009–2021 were identified using diagnosis codes. This approach was validated by a review of electronic health records. Associations between diet quality scores and the incidence of dementia were estimated using the Cox proportional hazards models, adjusted for potential confounders. Across a mean of 6.90 years of follow-up, we identified 408 incident cases of all-cause dementia. Having a higher diet quality was not significantly associated with a lower risk for incidents of all-cause dementia (adjusted HR for the highest compared with the lowest tertile: 1.01, 95% CI: 0.79, 1.29, P-trend = 0.95). Similarly, we did not observe a significant association between diet quality and altered risks of Alzheimer’s disease and other forms of dementia. Overall, having a higher diet quality was not significantly associated with a lower risk of dementia among the oldest old during the full follow-up.

Obesity increases the risk of developing type 2 diabetes, hypertension, and hyperlipidemia. We sought to determine the impact of obesity maintenance, weight regain, weight loss maintenance, and magnitudes of weight loss on future risk and time to developing these cardiometabolic conditions. This was a retrospective cohort study of adults receiving primary care at Geisinger Health System between 2001 and 2017. Using electronic health records, patients with ≥3-weight measurements over a 2-year index period were identified and categorized. Obesity maintainers (OM) had obesity (body mass index ≥30 kg/m²) and maintained their weight within ±3% from baseline (reference group). Both weight loss rebounders (WLR) and weight loss maintainers (WLM) had obesity at baseline and lost5% body weight in year 1; WLR regained ≥20% of weight loss by end of year 2 and WLM maintained ≥80% of weight loss. Incident type 2 diabetes, hypertension, and hyperlipidemia, and time-to-outcome were determined for each study group and by weight loss category for WLM. Of the 63,567 patients included, 67% were OM, 19% were WLR, and 14% were WLM. The mean duration of follow-up was 6.6 years (SD, 3.9). Time until the development of electronic health record-documented type 2 diabetes, hypertension, and hyperlipidemia was longest for WLM and shortest for OM (log-rank test p0.0001). WLM had the lowest incident type 2 diabetes (adjusted hazard ratio [HR] 0.676 [95% confidence interval [CI] 0.617 to 0.740]; p0.0001), hypertension (adjusted HR 0.723 [95% CI 0.655 to 0.799]; p0.0001), and hyperlipidemia (adjusted HR 0.864 [95% CI 0.803 to 0.929]; p0.0001). WLM with the greatest weight loss (15%) had a longer time to develop any of the outcomes compared with those with the least amount of weight loss (7%) (p0.0001). In an integrated delivery network population, sustained weight loss was associated with a delayed onset of cardiometabolic diseases, particularly with a greater magnitude of weight loss.

Introduction Sarcopenic obesity and its association with nonalcoholic fatty liver disease (NAFLD) is under‐recognized by many healthcare providers in Western medicine due to the lack of awareness and diagnostic guidelines. The result is delayed recognition and treatment, which leads to further health deterioration and increased healthcare costs. Sarcopenic obesity is characterized by the presence of increased fat mass in combination with muscle catabolism related to chronic inflammation and/or inactivity. Previous research has recommended evaluating body composition and physical function performance to adequately diagnose sarcopenic obesity. Body composition analysis can be performed by imaging applications through magnetic resonance imaging, computed tomography, and dual‐energy x‐ray absorptiometry. Due to the cost of each device and radiation exposure for patients as evidenced in all three modalities, bioelectrical impedance analysis offers a noninvasive approach capable of providing quick and reliable estimates of lean body and fat mass. Methods and Results This review analyzes the current evidence‐based literature, indicating a lower skeletal muscle mass and increased visceral adipose tissue correlation to the advancement of fibrosis in fatty liver disease. Conclusion Given the substantial promising research conducted in predominantly Asian populations regarding body tissue distribution and NAFLD, additional prospective research is needed to extend these findings in Western populations.

The presence of chronic low-grade inflammation, commonly identified in patients with severe obesity, alters iron homeostasis and indicators of iron status, fostering the development of updated guidelines for the diagnosis of iron deficiency (ID). Current recommended diagnostic thresholds for ID in obesity derived from expert opinion include a ferritin level of30 ng/mL and/or transferrin saturation (TSAT)20%. Earlier studies of ID among candidates for metabolic surgery using low levels of ferritin or iron as diagnostic thresholds demonstrated a prevalence of 5%-20%.Using the current recommended diagnostic thresholds for ID, this study measures the prevalence of ID in a large cohort of surgical candidates and its relationship to surgical outcomes.Geisinger Medical Center, Danville, Pennsylvania.The study cohort included 3,723 patients who underwent pre- operative nutritional assessment which included markers of iron nutrition over the period 2004-2018.The cohort included 2,988 women (80.3%) and 735 men (19.7%); body mass index: 49.4 ± 9 kg/mThe prevalence of ID among surgical candidates (45.4%) is more than twice that identified as ID in earlier studies. ID was commonly identified in the absence of anemia. The most severe ID was found in those with a serum ferritin level30 ng/mL and TSAT20%. ID in the presence of inflammation is often unrecognized and has implications regarding surgical outcomes after metabolic surgery.

Exome sequencing in hundreds of thousands of persons may enable the identification of rare protein-coding genetic variants associated with protection from human diseases like liver cirrhosis, providing a strategy for the discovery of new therapeutic targets.We performed a multistage exome sequencing and genetic association analysis to identify genes in which rare protein-coding variants were associated with liver phenotypes. We conducted in vitro experiments to further characterize associations.The multistage analysis involved 542,904 persons with available data on liver aminotransferase levels, 24,944 patients with various types of liver disease, and 490,636 controls without liver disease. We found that rare coding variants inRare germline mutations in

Low patient recruitment into diabetes prevention programs is a challenge. The primary aim of this study was to demonstrate that an increased recruitment rate can be achieved by communicating personalized risk of progression to type 2 diabetes, estimating risk reduction with weight loss, and offering program choice. Secondary aims included program participation rate, weight loss, and short-term decreased diabetes risk.In this single-arm study, persons with prediabetes from 3 primary care sites received a letter that communicated their personalized risk of progression to diabetes within 3-years, estimated risk reduction with 5, 10, 15 % weight loss, reported in pounds, and offered a choice of 5 free, 6-month, programs. A one-sided test was used to compare the recruitment rate against the maximum expected rate of (10 %).Recruitment response rate was 25.3 % (81/328, 95 % CI=[20.0 %, 29.4 %]) which was significantly higher than expected (p0.0001). Overall, 65 % of participants completed75 % of contacts. BMI, HbA1c, and diabetes risk (all p0.0001) improved at 6 months; BMI (p0.0001) and HbA1c (p0.05) improved at 12 months.Recruitment response rate was better than expected.Communicating personalized risk and reduction estimates with a choice of programs resulted in favorable outcomes, sustained at 1-year.

ObjectiveOne-third of American adults are estimated to have prediabetes but the vast majority are unaware. Accordingly, persons with prediabetes are equally unaware of their personal susceptibility of developing type 2 diabetes and the impact of weight loss on reducing the risk of progression. The primary aim of this study was to demonstrate that raising awareness of present risk, risk reduction, and offering available, accessible preventive interventions would result in fewer incidences of type 2 diabetes at 1- and 3-year follow-up periods. Secondary aims included clinician use of a novel diabetes risk calculator in primary care indicated by the proportion of patients being offered a preventive intervention.MethodsIn this single-arm study, persons with prediabetes from three primary care sites received a letter that communicated their personalized risk of progression to diabetes within three years; estimated risk reduction with 5, 10, 15% weight loss, reported in pounds, representing data illustrated in the diabetes risk calculator; and offered a choice of five free, 6-month, programs. Progression to type 2 diabetes was evaluated at 1- and 3-year follow-up periods using electronic health record data. Comparisons are made between the active participants and the non-respondent group. The diabetes risk calculator was implemented in 53 primary clinics in July 2020 and viewable in the electronic health record of persons with prediabetes without the need for clinician action. Electronic health record data were used to evaluate the rate of clinicians offering or referring persons with prediabetes to a preventive intervention—these rates of referral were compared between two phases (pre-implementation: 8/2019-2/2020; early implementation: 8/2020-2/2021).ResultsPersons with prediabetes (N=328) received letters and n=83 responded to the invitation to choose a preventive intervention (treatment). Follow-up data were available for n=55 treatment and n=169 non-respondents at 1- and 3-years. At 1-year follow-up, 2% of treatment and 20% of non-respondents developed type 2 diabetes (pConclusionProgression to type 2 diabetes was halted at 1- and 3-year follow-up for a significantly higher proportion of persons who received diabetes risk calculator results and initiated a preventive intervention compared to those who did not. In the early implementation phase, clinicians referred a higher proportion of persons with prediabetes to preventive intervention when presented with diabetes risk calculator results as compared the pre-implementation period.

Background: With the increasing focus of metabolomic methods on obesityrelated diseases, it is important to consider how sample handling may need to be adapted for the high compositions of lipids that can occur in such subjects. Introduction: High-lipid (cloudy, milky appearances; a.k.a. lipemic) biofluids are common in very high BMI subjects. Organic extractions of biofluids are useful for removing protein backgrounds, inactivating capsid viruses, and yielding relatively stable samples with excellent spectroscopic characteristics. This work considered how acetonitrile extractions, which are widely used, perform on lipemic sera. Results: In this technical note, we report the observation and remediation of a liquid-liquid phase separation in acetonitrile extractions of many lipemic sera. This unexpected behavior can be challenging to identify, especially if working with small volumes. The liquid-liquid separation shows a high miscibility of proteins in both liquid phases that impairs NMR data quality. We also report a simple temperature-based adaption of the acetonitrile extraction procedure that consistently results in a single aqueous phase and eliminates unwanted constituents. Conclusion: A robust approach to achieving reproducible, high quality samples of aqueous metabolites from lipemic sera from very high BMI subjects should be of utility in expanding metabolomics applications to lipemic biofluids.

Introduction Obesity accounts for a substantial and growing burden of disease globally. Body adiposity is highly heritable, and human genetic studies can lead to biological and therapeutic insights. Rationale Whole-exome sequencing of hundreds of thousands of individuals is complementary to approaches used to date in obesity genetics and has the potential to identify rare protein-coding variants with large phenotypic impact. We sequenced the exomes of 645,626 individuals from the UK, the US, and Mexico and estimated associations of rare coding variants with body mass index (BMI), a measure of overall adiposity used to define obesity in clinical practice. We complemented exome sequencing with fine-mapping of common alleles, polygenic score analysis, and in vitro and in vivo modeling work. Results We identified 16 genes for which the burden of rare nonsynonymous variants was associated with BMI at exome-wide statistical significance (inverse-variance weighted meta-analysis P < 3.6 × 10−7), including associations at five brain-expressed G protein–coupled receptors (CALCR, MC4R, GIPR, GPR151, and GPR75). We observed an overrepresentation of genes highly expressed in the hypothalamus, a key center for the neuroendocrine regulation of energy balance. Protein-truncating variants in GPR75 were found in ~4/10,000 sequenced people and were associated with 1.8 kg/m2 lower BMI, 5.3 kg lower bodyweight, and 54% lower odds of obesity in heterozygous carriers. Knock out of Gpr75 in mice resulted in resistance to weight gain in a high-fat diet model, which was allele-dose dependent (25% and 44% lower weight gain, respectively, for heterozygous Gpr75−/+ mice and knockout Gpr75−/− mice compared with wild type) and accompanied by improved glycemic control and insulin sensitivity. Protein-truncating variants in CALCR were associated with higher BMI and obesity risk, whereas protein-truncating variants in GIPR and two missense alleles [Arg190→Gln (Arg190Gln), Glu288Gly], which we show result in loss of function in vitro, were associated with lower adiposity. Among monogenic obesity genes in the leptin-melanocortin pathway, heterozygous predicted loss-of-function variants in LEP, POMC, PCSK1, and MC4R (but not LEPR) were associated with higher BMI. Rare protein-truncating variants in UBR2, ANO4, and PCSK1 were associated with more than twofold higher odds of obesity in heterozygous carriers, similar to predicted-deleterious nonsynonymous variants in MC4R, which are considered the most common cause of monogenic obesity. Polygenic predisposition due to >2 million common genetic variants influenced the penetrance of obesity in rare variant carriers in an additive fashion. Conclusion These results suggest that inhibition of GPR75 may be a therapeutic strategy for obesity and illustrate the power of massive-scale exome sequencing for the identification of large-effect coding variant associations and drug targets for complex traits.

Taste-signaling proteins, which are expressed throughout the digestive tract, are involved in regulating metabolism and immunity. This study aimed to determine if these genes are expressed and altered in jejunal tissues from patients with extreme obesity who received bariatric surgery. Reverse transcription polymerase chain reaction revealed that phospholipase C beta 2 and transient receptor potential channel M5 expression was downregulated in the jejunum of patients with a body mass index above 50, whereas gustducin expression remained unchanged. Our data suggest that taste-signaling dysregulation might contribute to obesity.

Background Non-alcoholic fatty liver disease (NAFLD) is characterized by changes in cell composition that occur throughout disease pathogenesis, which includes the development of fibrosis in a subset of patients. DNA methylation (DNAm) is a plausible mechanism underlying these shifts, considering that DNAm profiles differ across tissues and cell types, and DNAm may play a role in cell-type differentiation. Previous work investigating the relationship between DNAm and fibrosis in NAFLD has been limited by sample size and the number of CpG sites interrogated. Results Here, we performed an epigenome-wide analysis using Infinium MethylationEPIC array data from 325 individuals with NAFLD, including 119 with severe fibrosis and 206 with no histological evidence of fibrosis. After adjustment for latent confounders, we identified 7 CpG sites whose DNAm associated with fibrosis (p –8). Analysis of RNA-seq data collected from a subset of individuals (N = 56) revealed that gene expression at 288 genes associated with DNAm at one or more of the 7 fibrosis-related CpGs. DNAm-based estimates of cell-type proportions showed that estimated proportions of natural killer cells increased, while epithelial cell proportions decreased with disease stage. Finally, we used an elastic net regression model to assess DNAm as a biomarker of fibrotic stage and found that our model predicted fibrosis with a sensitivity of 0.93 and provided information beyond a model based solely on cell-type proportions. Conclusion These findings are consistent with DNAm as a mechanism underpinning or marking fibrosis-related shifts in cell composition and demonstrate the potential of DNAm as a possible biomarker of NAFLD fibrosis.

BACKGROUND: The extent to which obesity and genetics determine post-operative complications is incompletely understood. METHODS: We performed a retrospective study using two population cohorts with electronic health record (EHR) data. The first included 736,726 adults with body mass index (BMI) recorded between 1990-2017 at Vanderbilt University Medical Center. The second cohort consisted of 65,174 individuals from 12 institutions contributing EHR and genome-wide genotyping data to the Electronic Medical Records & Genomics (eMERGE) Network. Pairwise logistic regression analyses were used to measure the association of BMI categories with postoperative complications derived from International Classification of Disease-9 codes, including postoperative infection, incisional hernia, and intestinal obstruction. A genetic risk score (GRS) was constructed from 97 obesity-risk single nucleotide polymorphisms for a Mendelian randomization study to determine the association of genetic risk for obesity on postoperative complications. Logistic regression analyses were adjusted for sex, age, site, and race/principal components. RESULTS: Individuals with overweight or obese BMI (≥25 kg/m(2)) had increased risk for incisional hernia (Odds ratio [OR] 1.7-5.5, p

The oldest old (aged ≥80 years) are often the population subgroup at high nutritional risk due to age-related metabolic changes. We performed a validation analysis of a dietary screening tool (DST) which was developed for older adults among the oldest old. We examined dietary intakes using three 24-hour dietary recalls and the DST among 122 participants (aged 82-97) of the Geisinger Rural Aging Study. DST scores were compared with the Health Eating Index (HEI)-2015 scores, which were calculated based on three-day dietary recalls. Pearson correlations were used to characterize concurrent validity and Bland-Altman plots were used to identify potential bias. DST scores were significantly correlated with HEI scores (adjusted r = 0.68; p 0.001) in an age- and sex-adjusted model. Those within the not-at-risk DST group had significantly higher HEI scores (adjusted means = 79.6 ± 3.68) compared with those who were in the at-risk (adjusted means = 51.2 ± 1.56) and the possibly-at-risk (adjusted means = 66.3 ± 1.79) groups (p-trend0.001). The DST appears to be a valid measure of diet quality in the oldest old when compared with the HEI and may be a potential tool to assess overall diet quality in this population.

The worldwide increase in the prevalence of obesity and adiposity-related comorbidities has required a novel approach to cardiometabolic risk mitigation focused on the key mechanistic drivers of disease. The current manuscript presents the case of a 74-year-old male with obesity complicated by coronary artery disease, hypertriglyceridemia, hypertension, nonalcoholic fatty liver disease, obstructive sleep apnea, and type 2 diabetes. Expert panelists discuss optimal diagnostic and treatment strategies focused on lifestyle modifications including dietary interventions such as the Mediterranean dietary pattern, medications that target multiple drivers of disease, as well as procedural options.

More perceived physical fatigability and poor diet quality are associated with impairments in physical function in older adults. However, the degree to which more perceived fatigability explains the association between poor diet quality and low physical function is unknown. We examined this relationship in 122 (66F, 56M) of the oldest-old participants from the Geisinger Rural Aging Study (GRAS). We used 24-h dietary recalls to assess the Healthy Eating Index (HEI), the Pittsburgh Fatigability Scale (PFS, 0–50) to assess perceived physical fatigability, and the PROMIS Physical Function 20a* to assess physical function. We grouped participants into three age categories: 80–84 (n = 51), 85–89 (n = 51), and 90+ (n = 20) years. Multiple linear regression revealed that a lower HEI was associated with higher PFS Physical score after adjusting for age group, sex, body mass index, and the number of medical conditions (p = 0.001). Several macro- and micro-nutrient intakes were also lower in those reporting more (≥15) compared to less (&lt, 15) perceived physical fatigability. Mediation analysis revealed that PFS Physical scores explained ~65% (p = 0.001) of the association between HEI total score and PROMIS19 Physical Function score. Poor diet quality may contribute to more perceived physical fatigability, which could exacerbate impairments in the oldest-old’s physical function.

Background Several dietary components have been shown to be neuroprotective against risk of neurodegeneration. However, limited observational studies have examined the role of overall diet quality on risk of Parkinson's disease. Objectives We examined the associations between diet quality and risk of Parkinson's disease in a prospective cohort study and meta-analysis. Methods Included in the cohort study were 3,653 participants (1,519 men and 2,134 women; mean age: 81.5 years) in the Geisinger Rural Aging Study longitudinal cohort in Pennsylvania. Diet quality was assessed using a validated dietary screening tool containing 25 food- and behavior-specific questions in 2009. Potential Parkinson's cases were identified using electronic health records based on ICD9 (332.*), ICD10 (G20), and Parkinson-related treatments. Hazard ratios (HRs) and 95% confidence intervals (CIs) across diet quality tertiles were calculated using Cox proportional hazards models after adjusting for potential confounders. We further performed a meta-analysis by pooling our study with four published papers on this topic. Random-effects model was utilized to calculate the pooled risk ratios and 95% confidence intervals (CIs). Results During a mean of 6.94 years of follow-up, 47 incident Parkinson's cases were documented. Having high diet quality at baseline was associated with lower Parkinson's disease risk (adjusted HR for the highest vs the lowest diet quality tertile = 0.39; 95% CI: 0.17, 0.89; p-trend = 0.02). The meta-analysis including 140,617 individuals also showed that adherence to high diet quality or a healthy dietary pattern was associated with lower risk of Parkinson's disease (pooled risk ratio = 0.64; 95% CI: 0.49, 0.83). Conclusion Having high diet quality or a healthy dietary pattern was associated with lower future risk of Parkinson's disease.

The near universal presence of chronic low-grade systemic inflammation among patients with severe obesity disrupts iron homeostasis and underlies the association between obesity and iron deficiency. Immune activation and inflammation results in a reduction in circulating iron and diminished iron bioavailability for erythropoiesis. Inflammation also alters blood levels of commonly measured markers of iron nutrition status, which makes the diagnosis of iron deficiency difficult and has led to new recommendations regarding laboratory markers for the diagnosis. Recent evidence utilizing these newly recommended laboratory markers which include levels of ferritin, C Reactive Protein, and Transferrin Saturation suggests that the actual prevalence of iron deficiency among candidates for metabolic surgery may be double or triple the prevalence identified by low levels of ferritin alone. Thus, large numbers of surgical candidates have iron deficiency which has been heretofore largely unrecognized and inadequately treated. The assessment of iron status utilizing the currently recommended markers in the presence of chronic inflammatory diseases, and repletion of depleted stores for surgical candidates with deficiency during the pre-operative period presents an important opportunity for mitigating this condition in post-operative patients.

Bile acids have been implicated in the mechanism by which Roux-en-Y gastric bypass (RYGB) can induce remission of type 2 diabetes (T2D). Our goal was to identify circulating proteins whose levels changed after RYGB when dysglycemic parameters normalized.This was a retrospective study of 26 participants who underwent RYGB. Blood proteins were identified using two-dimensional electrophoresis and mass spectroscopy. Complement proteins were measured using immunoassays and bile acids measured using ultra-high-performance liquid chromatography and mass spectroscopy.A total of 7/452 blood proteins were found to change 2 days after RYGB. Complement component 3 (C3) was selected because of its regulation by bile acids and the glucoregulatory function of its proteolytically processed product C3adesArg or acylation-stimulating protein (ASP). The median (inter-quartile range/IQR) C3 level was 47.4 (34.5, 65.9) mg/dL before surgery decreasing to 40.9 (13.4, 64.1) mg/dL within 2 days after surgery (p = 0.0292). The median (IQR) ASP level increased from 2.8 (0.9, 7.3) nM before surgery to 8.0 (5.3, 14.1) nM within 2 days after surgery (p = 0.0016). ASP levels increased in 14/17 (82%) with T2D remission and in 6/6 with normoglycemia but decreased in 3/3 with persistent T2D. Of ten bile acids measured, the levels of ursodeoxycholic acid (UDCA) were significantly decreased after RYGB and the levels of taurodeoxycholic acid (TDCA) were significantly decreased with T2D remission.These data further support an association of C3 with glucose metabolism and implicate bile acids and ASP in the early remittive effects of RYGB on T2D.

A real-time trial of a cancer blood test Cancers diagnosed early are often more responsive to treatment. Blood tests that detect molecular markers of cancer have successfully identified individuals already known to have the disease. Lennon et al. conducted an exploratory study that more closely reflects the way in which such blood tests would be used in the future. They evaluated the feasibility and safety of incorporating a multicancer blood test into the routine clinical care of 10,000 women with no history of cancer. Over a 12-month period, the blood test detected 26 cancers of different types. A combination of the blood test and positron emission tomography–computed tomography (PET-CT) imaging led to surgical removal of nine of these cancers. Use of the blood test did not result in a large number of futile follow-up procedures. Science , this issue p. eabb9601

Summary Objective The purpose of this study was to compare body composition measurements estimated by multi‐frequency bioelectrical impedance analysis (MF‐BIA) with air displacement plethysmography (ADP) in individuals with obesity. Methods Bariatric patients were recruited from Geisinger's Center for Nutrition and Weight Management Clinic in Danville, Pennsylvania. Sixty‐two participants (age = 52.4 ± 9.3 years; body mass index = 38.9 ± 8.0 kg m−2) reported for a same‐day testing visit. Body composition was measured using a common MF‐BIA analyzer (InBody 720, Biospace Co., Beverly Hills, CA) and ADP. Results Strong relationships were observed between MF‐BIA and ADP methods (r = 0.88–0.96, P

Objective: This study aims to assess the efficacy and safety of Gelesis100, a novel, nonsystemic, superabsorbent hydrogel to treat overweight or obesity.Methods: The Gelesis Loss Of Weight (GLOW) study was a 24-week, multicenter, randomized, double-blind, placebo-controlled study in patients with BMI ≥ 27 and ≤ 40 kg/m2 and fasting plasma glucose ≥ 90 and ≤ 145 mg/dL. The co-primary end points were placebo-adjusted weight loss (superiority and 3% margin super-superiority) and at least 35% of patients in the Gelesis100 group achieving ≥ 5% weight loss.Results: Gelesis100 treatment caused greater weight loss over placebo (6.4% vs. 4.4%, P = 0.0007), achieving 2.1% superiority but not 3% super-superiority. Importantly, 59% of Gelesis100-treated patients achieved weight loss of ≥ 5%, and 27% achieved ≥ 10% versus 42% and 15% in the placebo group, respectively. Gelesis100-treated patients had twice the odds of achieving ≥ 5% and ≥ 10% weight loss versus placebo (adjusted OR: 2.0, P = 0.0008; OR: 2.1, P = 0.0107, respectively), with 5% responders having a mean weight loss of 10.2%. Patients with prediabetes or drug-naive type 2 diabetes had six times the odds of achieving ≥ 10% weight loss. Gelesis100 treatment had no apparent increased safety risks.Conclusions: Gelesis100 is a promising new nonsystemic therapy for overweight and obesity with a highly desirable safety and tolerability profile.

The current popularity of metabolic surgery has led to increasing attention to long-term nutritional complications.The purpose of this retrospective study is to accurately define the long-term incidence of clinically significant anemia after Roux-en-Y gastric bypass (RYGB) and to identify factors that contribute to increased risk.The study cohort consisted of 2116 patients who underwent RYGB with necessary laboratory information available, and with longitudinal follow-up available (mean 5.3 ± 3.3 yr). A concurrent cohort of nonoperated patients matched for age, sex, body mass index, and baseline hemoglobin was identified (N = 1126). The RYGB and control cohorts were followed longitudinally to estimate the percent that develop mild, moderate, or severe anemia using Kaplan-Meier analysis. Predictors of severe anemia within the RYGB cohort were identified using Cox regression.The percent developing postRYGB mild, moderate, and severe anemia was 27%, 9%, and 2% at 1 year postRYGB and increased to 68%, 33%, and 11% at 5 years postRYGB. As compared with the nonoperated control cohort, the RYGB cohort was more likely to develop mild anemia (hazard ratio [HR] = 1.36, P.001), moderate anemia (HR = 1.75, P.001), and severe anemia (HR = 1.87, P.001). Severity of anemia was associated with an increasing percentage of microcytosis (P.0001). Clinical factors independently associated with an increased risk of severe anemia within the RYGB cohort included females and males40 years of age (HR = 2.97, 95% confidence interval [CI] = 1.14, 7.75, P = .026), preoperative anemia (HR = 1.65, 95% CI = 1.19, 2.29, P = .0029), preoperative low ferritin level (HR = 2.28, 95% CI = 1.39, 3.74, P = .0029), and a rapid 6-month weight loss trajectory (HR = 1.71, 95% CI = 1.22, 2.38, P = .0018).The long-term incidence of clinically significant anemia after RYGB is alarmingly high and warrants more detailed study.

Altered DNA methylation events contribute to the pathogenesis and progression of metabolic disorders, including nonalcoholic fatty liver disease (NAFLD). Investigations of global DNA methylation patterns in liver biopsies representing severe NAFLD fibrosis have been limited. We used the HumanMethylation 450K BeadChip to analyze genome-wide methylation in patients with biopsy-proven grade 3/4 NAFLD fibrosis/cirrhosis (N = 14) and age- and sex-matched controls with normal histology (N = 15). We identified 208 CpG islands (CGIs), including 99 hypomethylated and 109 hypermethylated CGIs, showing statistically significant evidence (adjusted P value

Total Knee Arthroplasty (TKA, also known as total knee replacement) is a highly effective surgical intervention for the restoration of physical function and improving quality of life in patients with disabling knee osteoarthritis. Recent data suggest that obesity is a major risk factor in the pathogenesis and progression of knee osteoarthritis, with increases in body mass index (BMI, kg/m2) directly correlating with the prevalence of knee osteoarthritis. However, recent data also suggest that there are increased risks associated with TKAs when performed in patients with morbid obesity (BMI > 40 kg/m2). Patients with morbid obesity are routinely referred for weight management prior to surgery. Many of these patients fail to meet the recommended weight loss goals prior to TKA, potentially making them ineligible for surgery or placing them at increased risk for sub-optimal outcomes. Thus, the purpose of this study is to examine the potential therapeutic impact and long-term outcomes of surgically induced weight loss on TKA outcomes. Specifically, these outcomes will include measures of physical function, mobility, and indices of joint function at 1 and 2 years post-TKA compared between extremely obese patients who undergo TKA (Control group, n = 150) and those with TKA performed ~1 year after bariatric surgery (Test group, n = 150). An additional primary endpoint will be the percent of bariatric patients that negate or delay the need for TKA. Secondary endpoints include perioperative outcomes after TKA.

Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85–0.92, p = 6.3 × 10−10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49–0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D., Genetic variation in ANGPTL4 is associated with lipid traits. Here, the authors find that predicted loss-of-function variants in ANGPTL4 are associated with glucose homeostasis and reduced risk of type 2 diabetes and that Angptl4−/− mice on a high-fat diet show improved insulin sensitivity.

AIMS/HYPOTHESIS: Targeting regulators of adipose tissue lipoprotein lipase could enhance adipose lipid clearance, prevent ectopic lipid accumulation and consequently ameliorate insulin resistance and type 2 diabetes. Angiopoietin-like 8 (ANGPTL8) is an insulin-regulated lipoprotein lipase inhibitor strongly expressed in murine adipose tissue. However, Angptl8 knockout mice do not have improved insulin resistance. We hypothesised that pharmacological inhibition, using a second-generation antisense oligonucleotide (ASO) against Angptl8 in adult high-fat-fed rodents, would prevent ectopic lipid accumulation and insulin resistance by promoting adipose lipid uptake. METHODS: ANGPTL8 expression was assessed by quantitative PCR in omental adipose tissue of bariatric surgery patients. High-fat-fed Sprague Dawley rats and C57BL/6 mice were treated with ASO against Angptl8 and insulin sensitivity was assessed by hyperinsulinaemic–euglycaemic clamps in rats and glucose tolerance tests in mice. Factors mediating lipid-induced hepatic insulin resistance were assessed, including lipid content, protein kinase Cε (PKCε) activation and insulin-stimulated Akt phosphorylation. Rat adipose lipid uptake was assessed by mixed meal tolerance tests. Murine energy balance was assessed by indirect calorimetry. RESULTS: Omental fat ANGPTL8 mRNA expression is higher in obese individuals with fatty liver and insulin resistance compared with BMI-matched insulin-sensitive individuals. Angptl8 ASO prevented hepatic steatosis, PKCε activation and hepatic insulin resistance in high-fat-fed rats. Postprandial triacylglycerol uptake in white adipose tissue was increased in Angptl8 ASO-treated rats. Angptl8 ASO protected high-fat-fed mice from glucose intolerance. Although there was no change in net energy balance, Angptl8 ASO increased fat mass in high-fat-fed mice. CONCLUSIONS/INTERPRETATION: Disinhibition of adipose tissue lipoprotein lipase is a novel therapeutic modality to enhance adipose lipid uptake and treat non-alcoholic fatty liver disease and insulin resistance. In line with this, adipose ANGPTL8 is a candidate therapeutic target for these conditions.

Objective Determine the impact of long-term non-surgical weight loss maintenance on clinical relevance for osteoarthritis, cancer, opioid use, and depression/anxiety and healthcare resource utilization. Methods A cohort of adults receiving primary care within Geisinger Health System between 2001–2017 was retrospectively studied. Patients with ≥3 weight measurements in the two-year index period and obesity at baseline (BMI ≥30 kg/m2) were categorized: Obesity Maintainers (reference group) maintained weight within +/-3%; Weight Loss Rebounders lost ≥5% body weight in year one, regaining ≥20% of weight loss in year two; Weight Loss Maintainers lost ≥5% body weight in year one, maintaining ≥80% of weight loss. Association with development of osteoarthritis, cancer, opioid use, and depression/anxiety, was assessed; healthcare resource utilization was quantified. Magnitude of weight loss among maintainers was evaluated for impact on health outcomes. Results In total, 63,567 patients were analyzed including 67% Obesity Maintainers, 19% Weight Loss Rebounders, and 14% Weight Loss Maintainers; median follow-up was 9.7 years. Time until osteoarthritis onset was delayed for Weight Loss Maintainers compared to Obesity Maintainers (Logrank test p 15% weight loss was associated with the greatest decrease in incident osteoarthritis. Healthcare resource utilization was significantly higher for Weight Loss Rebounders and Maintainers compared to Obesity Maintainers. Increased weight loss among Weight Loss Maintainers trended with lower overall healthcare resource utilization, except for hospitalizations. Conclusions In people with obesity, sustained weight loss was associated with greater clinical benefits than regained short-term weight loss and obesity maintenance. Higher weight loss magnitudes were associated with delayed onset of osteoarthritis and led to decreased healthcare utilization.